Role of Complement Receptor 1 in the Modulation of B Cell Tolerance

补体受体 1 在 B 细胞耐受调节中的作用

基本信息

批准号：
10806147
负责人：
SUSAN A. BOACKLE
金额：
--
依托单位：
VA EASTERN COLORADO HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-10-01 至 2022-11-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10806147
关键词：
1q32 ATAC-seq Acceleration Address Affect Antigens Autoantibodies Autoantigens Autoimmune Diabetes Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Bone Marrow Caring Cell physiology Cells Chimera organism Chromosomes Communities Complement 3b Complement 3d Receptors Complement Receptor Complement component C5 Cytoprotection Data Department of Defense Development Diabetes Mellitus Disease Early treatment Effector Cell Environmental Risk Factor Exposure to FRAP1 gene Female Future Genes Genetic Genetic Transcription Goals Health Health Care Costs Heart Diseases Immune Immune Tolerance Immune system Immunologics Immunosuppression Impairment Inbred NOD Mice Incidence Individual Inflammatory Intervention Introns Kidney Failure Ku70 protein Ligation Lupus Macrophage-1 Antigen Malignant Neoplasms Maps Measures Membrane Military Personnel Minority Minority Women Modeling Morbidity - disease rate Onset of illness Organ Pathogenicity Pathway interactions Patient Care Phase Phenotype Population Population Projection Process Regulatory Element Risk Risk Reduction Role Severities Single Nucleotide Polymorphism Specificity Stimulus Symptoms Syndrome System Systemic Lupus Erythematosus Testing Therapeutic Toxic effect Transcript Variant Veterans Woman active duty case control demographics ds-DNA genetic variant immunoregulation infection risk military veteran minority children mortality mouse model novel therapeutic intervention overexpression post-traumatic stress pre-clinical prevent protective effect systemic autoimmune disease transcription factor trend young woman

项目摘要

Autoimmune diseases affect more than 2% of the US population, with effects on morbidity and mortality and associated health care costs that rival those of cancer and heart disease. Both genetic and environmental factors influence the development of autoimmune diseases, which result from an imbalance between activation and regulation of the immune system. As our understanding of the immunological mechanisms that drive these diseases has grown, the impetus has been to develop specific therapies that restore immune tolerance to disease-associated autoantigens. We recently identified by trans-ancestral mapping a single nucleotide polymorphism (SNP), rs1876453, located just inside the first intron of the immune-associated complement receptor 2 (CR2) gene that was enriched in controls rather than lupus cases, suggesting that it had a protective effect. CR2 is located directly 5’ of complement receptor 1 (CR1) at chromosome 1q32. We found that B cells from individuals with the protective SNP had increased transcription of the CR1 gene but no changes in CR2 transcriptional levels. We hypothesize that increased transcription of CR1 associated with the protective CR2 SNP results in the active induction of antigen-specific immune tolerance. We will evaluate the mechanism for this using several immunological and transcriptional approaches and ultimately test whether forced overexpression of CR1 restores tolerance in a model of systemic lupus erythematosus. We propose that CR1 is a viable target for the early treatment of lupus and other autoimmune diseases during the preclinical phase in which autoantibodies are present in the absence of symptoms. With rising enlistment into the military of young minority women who are at increased risk of developing lupus, the future extension of our findings into tangible interventions will have a substantial impact on veteran health.

自身免疫性疾病影响美国人口的2％以上，对发病率和死亡率以及相关的医疗保健损害了癌症和心脏病的风险。遗传和环境因素影响自身免疫性疾病的发展，这是由于激活之间的不平衡而导致的和免疫机制的调节。作为我们对驱动这些免疫机制的理解疾病已经成长，动力是开发出恢复免疫耐受性的特定疗法与疾病相关的自身抗原。我们最近通过跨义映射单个核苷酸来识别多态性（SNP），RS1876453，位于免疫相关完成的第一个内含子内部接收器2（CR2）基因富含对照而不是狼疮病例，表明它具有受保护影响。 CR2位于1q32染色体上的补体受体1（CR1）的5'。我们发现B细胞受保护SNP的个体的转录增加了CR1基因，但CR2没有变化转录水平。我们假设增加了与受保护CR2相关的CR1转录 SNP导致积极诱导抗原特异性免疫耐受性。我们将评估机制这使用了几种免疫学和转录方法，并最终测试是否强制 CR1的过表达恢复了系统性红斑狼疮模型中的公差。我们建议CR1 是临床前阶段早期治疗狼疮和其他自身免疫性疾病的可行目标在没有症状的情况下存在自身抗体。随着入伍的军事年轻的少数民族妇女患狼疮的风险增加，我们的发现的未来扩展到有形干预措施将对退伍军人健康产生重大影响。